ASTM E2097-00(2006)
(Guide)Standard Guide for Determining the Impact of Extractables from Non-Metallic Materials on the Safety of Biotechnology Products
Standard Guide for Determining the Impact of Extractables from Non-Metallic Materials on the Safety of Biotechnology Products
SIGNIFICANCE AND USE
This guide applies to the determination of the safety of non-metallic materials used in contact with biotechnology product containing solutions. Process materials leach low level of residues into water, cell culture media, buffers, and other product containing solutions. This document offers guidance on determining the safety of these materials (process materials) for use. The goal is to prevent toxic extractables from entering process streams and ultimately contaminating the final product in unacceptable levels.
The purpose of this guide is to describe tests to qualify materials with respect to any extractable substances so as to prevent unintentional introduction of a potential source of objectionable substances. An extractable material is objectionable if it is toxic, interacts with product constituents, interferes with required assays, or otherwise affects the process stream so as to adversely affect critical quality parameters, for example, purity, safety, efficacy, identity, strength of the final product or its successful production. All organizations producing pharmaceutical products should consider the points in this guide when qualifying process materials for use in their production processes.
This guide outlines the application of the process material tests primarily in ASTM or USP. Typical process materials include high molecular weight polymers and solids such as hoses, filters, filter housings, containers, valve diaphragms, gaskets, o-rings, chromatography resins, and chromatographic columns.
The battery of tests described in this guide is intended to cover a wide variety of potential attributes of materials and to characterize possible extractables.
The material specification will vary depending on the impact on the final product and the point in the process that the product solution contacts the material. Tighter specifications should be considered for extractables for final product purification process materials than for fermentation media pr...
SCOPE
1.1 This guide covers procedures and test methods for process component qualification by the end user. The goal is to assess the safety impact of extractables from non-metallic process components used in contact with bioprocessing solutions. This encompasses the impact of extractables on the safety of the final product as it passes through the various stages of the manufacturing process. This guide is not designed for evaluation of metallic materials, final product container/closures or those components intentionally added to the product or production streams during the manufacturing process. Testing of solids and extracts is specified in other ASTM standards. Materials must be qualified by specific use.
1.2 The values stated in SI units are to be regarded as the standard.
1.3 There is no companion guide available.
1.4 Safety/Fire hazards: Extractions with organic solvents will be infrequent under this Guide, but, when used must be treated as potential fire/explosion hazards.
1.5 This guide does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.
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Designation: E2097 − 00(Reapproved 2006)
Standard Guide for
Determining the Impact of Extractables from Non-Metallic
Materials on the Safety of Biotechnology Products
This standard is issued under the fixed designation E2097; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope 3. Terminology
1.1 This guide covers procedures and test methods for
3.1 See the Dictionary of Engineering Science and Technol-
process component qualification by the end user.The goal is to ogy. Review with Subcommittee E48.91 on Terminology. See
assess the safety impact of extractables from non-metallic
Section A7 on Terminology and Part E on Terminology in
process components used in contact with bioprocessing solu- ASTM Standards in Form and Style for ASTM Standards for
tions. This encompasses the impact of extractables on the
details.
safety of the final product as it passes through the various
3.2 Definitions:
stagesofthemanufacturingprocess.Thisguideisnotdesigned
3.2.1 biopharmaceutical—any drug product produced from
for evaluation of metallic materials, final product container/
living organisms.
closures or those components intentionally added to the prod-
3.2.2 biotechnology solution—a solution containing or pro-
uct or production streams during the manufacturing process.
ducing products from living microbial, animal or plant cells or
Testing of solids and extracts is specified in other ASTM
by the enzymes from those cells.
standards. Materials must be qualified by specific use.
3.2.3 biotechnology product—a discrete chemical entity
1.2 The values stated in SI units are to be regarded as the
producedbygrowingsinglecellorganismswithuniquegenetic
standard.
information.
1.3 There is no companion guide available.
3.2.4 elution cytotoxicity—see USP.
1.4 Safety/Fire Hazards: Extractions with organic solvents
3.2.5 emission spectrographic analysis (ESA)— an analyti-
will be infrequent under this guide, but, when used must be
cal technique for determining metals in a sample vaporized in
treated as potential fire/explosion hazards.
a plasma arc.
1.5 This standard does not purport to address all of the
3.2.6 extractables—residues from solid process components
safety concerns, if any, associated with its use. It is the
not intentionally part of the product process stream.
responsibility of the user of this standard to establish appro-
3.2.7 fermentation—the biochemical reaction process where
priate safety and health practices and determine the applica-
microorganisms in a nutrient medium convert a feedstock to a
bility of regulatory limitations prior to use.
product.
2. Referenced Documents
3.2.8 inductively coupled plasma (ICP)—an analytical tech-
nique designed to quantitate chemical elements.
2.1 ASTM Standards:
D4951 Test Method for Determination ofAdditive Elements
3.2.9 materials of construction—high molecular weight or
in Lubricating Oils by Inductively Coupled Plasma
solid materials, used in biopharmaceutical process equipment
Atomic Emission Spectrometry
which contact process solutions and can potentially release
F619 Practice for Extraction of Medical Plastics
extractable residues.
3.2.10 non-volatile residue (NVR)—non-volatile material
remaining after evaporating a solvent into which the residue
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
has been extracted (see USP).
of Pharmaceutical Products and is the direct responsibility of Subcommittee E55.04
on General Biopharmaceutical Standards.
3.2.11 oxidizable substances (OS)—chemical compounds
Current edition approved Nov. 1, 2006. Published December 2006. Originally
which may be oxidized by potassium permanganate under
approved in 2000. Last previous edition approved in 2000 as E2097 – 00. DOI:
specified conditions (see USP).
10.1520/E2097-00R06.
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
3.2.12 product contact material—a material which physi-
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
cally contacts a solution containing the chemical entity desig-
Standards volume information, refer to the standard’s Document Summary page on
the ASTM website. nated the product.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2097 − 00 (2006)
3.2.13 process materials—high molecular weight or solid functional product contact materials predicted to be suitable
materials which contact process solutions potentially releasing based on manufacturer specifications. Choose materials which
extractable residues. have specifications defined by pharmaceutical compendia to
the extent possible. The goal is to find and use materials that
3.2.14 purification—the process by which the desired prod-
will permit an acceptable level of extractables into the process
uct is separated from the production process solution.
solution. Materials should be approved by specific process use.
3.2.15 residue on ignition (ROI)—the residue remaining
Awritten protocol should be prepared outlining the tests to be
after ashing a material at high temperature.
done on each process material qualified. Qualified materials
3.2.16 total organic carbon (TOC)—an analytical technique
must be well defined and documented to assure equivalent
for measuring the carbon associated with organic molecules in
replacements may be obtained.Vendor audits are necessary for
a solution.
all suppliers of product contact material with significant
extractables.
4. Significance and Use
6.2 When a high quality, functional material is identified,
4.1 This guide applies to the determination of the safety of
subject it to the following procedure as part of the validation of
non-metallic materials used in contact with biotechnology
the process.
product containing solutions. Process materials leach low level
6.3 Choose the production function from Table 1. Use
of residues into water, cell culture media, buffers, and other
already validated ASTM or USP test methods wherever pos-
product containing solutions. This document offers guidance
sible. If the product is to be licensed in a country with other
ondeterminingthesafetyofthesematerials(processmaterials)
compendial requirements, those will have to be considered as
for use. The goal is to prevent toxic extractables from entering
well. If test methods are the same but limits are different, use
process streams and ultimately contaminating the final product
the more stringent limits.
in unacceptable levels.
NOTE 1—The cumulative effect of the ongoing removal of extractables
4.2 The purpose of this guide is to describe tests to qualify
can potentially affect the performance of plastics in certain applications.
materials with respect to any extractable substances so as to
prevent unintentional introduction of a potential source of 6.4 Perform the tests designated in Table 1. Where extrac-
tions are done, follow Practice F619 – 79 (1991). Increase the
objectionable substances.An extractable material is objection-
time, temperature and concentration of the extraction several
able if it is toxic, interacts with product constituents, interferes
with required assays, or otherwise affects the process stream so foldbeyondproductionconditionstobuildinsafetyfactorsand
insure worst case. Also it may be appropriate to exacerbate
as to adversely affect critical quality parameters, for example,
purity, safety, efficacy, identity, strength of the final product or other factors affecting the extraction capability of the solvent
such as organic concentration and pH. Demonstration of
its successful production.All organizations producing pharma-
ceutical products should consider the points in this guide when depletion of extractable material can be shown by repeated
extraction and testing for non-volatile residue or oxidizable
qualifying process materials for use in their production pro-
cesses. substances.
6.5 Characterize the product contact process material by
4.3 This guide outlines the application of the process
through the film, pyrolysis, attenuated total reflectance or
material tests primarily in ASTM or USP. Typical process
solution infrared methods. The infrared scan will become the
materials include high molecular weight polymers and solids
reference for subsequent lots of the material unless a manu-
such as hoses, filters, filter housings, containers, valve
facturer or other valid scan is available.
diaphragms,gaskets,o-rings,chromatographyresins,andchro-
matographic columns.
6.6 Evaluate the product contact process material for heavy
metals using Residue on Ignition followed by Emission Spec-
4.4 Thebatteryoftestsdescribedinthisguideisintendedto
trographic or Inductively Coupled Plasma methodologies. In
cover a wide variety of potential attributes of materials and to
this case the amount of Residue on Ignition is not important
characterize possible extractables.
except as it allows you to calculate the concentration of metals
4.5 The material specification will vary depending on the
in the solid. If unacceptable levels of heavy metals are found,
impact on the final product and the point in the process that the
appropriate extracts should be tested by Atomic Absorption
product solution contacts the material. Tighter specifications
Spectroscopy to determine if the metals are extractable into the
should be considered for extractables for final product purifi-
relevant process solution.
cation process materials than for fermentation media process
6.7 Distilled Water Extract—Follow Practice F619 –79
materials.
(1991), Sections 6 through 12. When choosing a set of
5. Reagents
extractionconditions,chooseatemperaturesimilartotheworst
case use conditions. Extend the extraction time as appropriate
5.1 The quality of reagents used for the procedures indi-
to create safety factors.
cated in this guide are specified in the test standards referenced
6.7.1 Oxidizable Substances—results will normally be sig-
(for example, ASTM and USP).
nificantly higher than USP Purified Water limits.
6. Procedure
6.7.2 Total Organic Carbon—measurements are very sen-
6.1 During research and development to define the manu- sitive and may be used in place of oxidizable substances in
facturing process for a desired biotechnology product, select organic free solvents.
E2097 − 00 (2006)
TABLE 1 Recommended Tests on Non-Soluble, Non-M
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